This proposal outlines an integrative five year training program for the candidate, Ronadip R. Banerjee, M.D., Ph.D., in his development as a physician-scientist towards becoming an independent investigator. Dr. Banerjee's research proposal, investigating the role of glucocorticoids in the development and function of the endocrine pancreas, will be carried out in the laboratory of Dr. Seung Kim, Professor of Developmental Biology and Howard Hughes Investigator at Stanford University. The research plan explores the hypothesis that glucocorticoids regulate the development and function of the endocrine pancreas by inhibiting growth, and suppressing hormone secretion and gene expression. This hypothesis is evaluated by three Specific Aims: (1) to determine the role of GCs in the development and postnatal expansion of the endocrine pancreas, (2) to elucidate the metabolic consequences of inactivating GC signaling in islets in postnatal and adult periods, and (3) to evaluate the consequences of abolishing GC signaling in islets to the metabolic stress response by using environmental and pharmacologic models of glucocorticoid excess. To accomplish these Aims, the project uses the "Cre-Lox" system to generate conditional "knockout" genetic models in mice. Metabolic phenotyping, in conjunction with specialized cell and molecular analyses will ascertain the physiologic consequences of the cell-type-specific conditional deletion of GR at a molecular level. Accomplishment of these Aims should identify how glucocorticoids directly regulate islet growth and function. Additionally, this project should provide insight into the molecular underpinnings of glucocorticoid-induced diabetes, and identify specific molecular defects that may present novel therapeutic targets in diabetes treatment. Concurrently, Dr. Banerjee will complete structured career development training supervised by an Advisory Committee comprised of leading physician-scientists and mentors within the Stanford Endocrinology and Metabolism division. These will include didactic, clinical, teaching, and managerial experience necessary to achieve his long-term goal of becoming a well-rounded physician-scientist capable of running a research laboratory at a leading academic medical center. PUBLIC HEALTH RELEVANCE: Diabetes, which afflicts as many as 25 million people in the United States today, is a leading cause of death, and morbidity, including blindness, heart disease, stroke, and kidney disease. Clearly, it is a major public health problem. One of the major defects in diabetes is the failure of the pancreas to produce enough insulin to match the increased blood glucose levels. Our proposal investigates how "stress" hormones, called glucocorticoids, might directly disrupt the normal growth and function of the hormone-producing cells of the pancreas. Understanding this process may lead to new therapies directed specifically at the pancreas dysfunction that is a cornerstone of the diabetic disease process.